The present invention relates to a process for the metallation of a carbocyclic aromatic derivative.
The invention is preferably directed towards the ortho-metallation of 1,3-dimethoxybenzene and more particularly to the preparation of 2,6-dimethoxybenzoic acid.
An o-metallation conventionally denotes a reaction leading to the generation of an anion in an ortho position relative to an electron-donating group present on an aromatic system.
More specifically, the present invention relates to an electrophilic addition to aromatic systems bearing an anion. This mechanism requires, in a first step, the loss of a leaving group, commonly a proton, prior to the addition of the electrophilic group which takes place in a consecutive step.
One of the approaches conventionally adopted for carrying out the first step consists in placing the aromatic derivative which it is desired to functionalize in contact with an organometallic compound in order to metallate it.
The usual reagent proposed for this reaction is butyllithium.
The major drawback of this metallation is precisely the use of butyllithium, which is an expensive reagent.
The reaction of sodium on 1,3-dimethoxybenzene in the presence of chlorobenzene, followed by a carboxylation has also been disclosed (G. Erhardt; Chem. Ber. 2042 (1963)). However, the reaction yield in terms of expected product remains very low on account of the formation of side products.
The object of the present invention is thus to propose a novel route for the metallation of aromatic derivatives which is more advantageous in terms of cost and yield than those mentioned above.
Consequently, a first subject of the present invention is a process for the ortho-metallation of a carbocyclic aromatic derivative bearing at least one electron-donating group, characterized in that the said carbocyclic aromatic derivative is reacted with an effective amount of at least one alkali metal in the presence of a compound of formula (I):
RXxe2x80x83xe2x80x83(I)
in which
R represents a hydrocarbon-based radical containing from 1 to 20 carbon atoms which may be a saturated or unsaturated, linear or branched acyclic aliphatic radical; a saturated, unsaturated, monocyclic or polycyclic cycloaliphatic radical; or a saturated or unsaturated, linear or branched aliphatic radical bearing a cyclic substituent; and
X represents a bromine or chlorine atom.
In the account which follows of the present invention, the term xe2x80x9caromaticxe2x80x9d means the conventional notion of aromaticity as defined in the literature, in particular by Jerry March, Advanced Organic Chemistry, 4th edition, John Wiley and Sons, 1992, pp. 40 et seq.
More specifically, a subject of the present invention is a process for the ortho-metallation of a carbocyclic aromatic derivative of general formula (II): 
in which:
A symbolizes the residue of a ring forming all or part of a monocyclic or polycyclic aromatic carbocyclic system, this system comprising at least one group Rxe2x80x2, the said cyclic residue possibly bearing one or more substituents,
Rxe2x80x2 represents one or more substituents, which may be identical or different, of electron-donating nature, which are optionally linked together, and
n is a non-zero integer less than or equal to 4.
The electron-donating nature of the radicals Rxe2x80x2 is assessed in the context of the present invention according to the scale of electronegativity established by Jerry March, xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th edition, John Wiley and Sons, 1992, pp. 14 et seq. The electronegative nature of a radical is evaluated with regard to that of the hydrogen atom, the value of which is 2.176.
As an illustration of the radicals which may be represented by Rxe2x80x2 in the general formula (II), mention may be made in particular of:
a linear or branched alkyl radical containing from 1 to 12 carbon atoms, the hydrocarbon-based chain possibly being interrupted with a hetero atom (for example oxygen), with a functional group (for example xe2x80x94COxe2x80x94) and/or bearing a substituent such as, for example, an aromatic or non-aromatic cyclic substituent. It may be in particular a linear or branched alkyl radical containing from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, or a linear or branched alkenyl radical containing from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms, such as vinyl or allyl, or a C1 to C12 arylalkyl radical such as benzyl,
a carbocyclic radical which is saturated or which comprises 1 or 2 unsaturations in the ring, generally containing from 3 to 8 carbon atoms and preferably 6 carbon atoms in the ring, the said ring possibly being substituted with substituents such as Rxe2x80x2. It may be in particular a cycloalkyl group containing from 3 to 8 carbon atoms, such as a cyclohexyl group, and
an aromatic carbocyclic radical, preferably a monocyclic radical, generally containing at least 4 carbon atoms and preferably 6 carbon atoms in the ring, the said ring possibly being substituted. It may in particular be phenyl;
Z(R1) with Z representing an oxygen or sulphur atom and R1 corresponding to the definition proposed for Rxe2x80x2 above and preferably featuring
a hydrogen atom,
a linear or branched C1 to C6 and preferably C1 to C4 alkyl radical such as methyl, ethyl, propyl, ispropyl, butyl, isobutyl, sec-butyl or tert-butyl;
a C3 to C8 cycloalkyl radical such as cyclohexyl;
a fused or non-fused C5 to C12 aryl radical such as phenyl;
a C1 to C12 arylalkyl radical such as benzyl, and
a trialkylsilyl radical,
xe2x80x94R2COOR1,
xe2x80x94R2COxe2x80x94N(R3)2,
xe2x80x94R2xe2x80x94N(R3)2,
xe2x80x94R2xe2x80x94CF3;
with R2 representing a valency bond or a linear or branched, saturated or unsaturated divalent hydrocarbon-based radical containing from 1 to 6 carbon atoms, such as, for example, methylene, ethylene, propylene, isopropylene or isopropylidene, and the radicals R3, which may be identical or different, representing a hydrogen atom or a linear or branched alkyl radical containing from 1 to 6 carbon atoms, or alternatively
two groups Rxe2x80x2 can be linked and form alkylenedioxy or alkylenedithio groups, preferably a methylenedioxy, ethylenedioxy, methylenedithio or ethylenedithio group.
It is understood that the list of examples of substituents Rxe2x80x2 given above has no limiting nature. Any substituent can be present on the ring provided that it remains inert under the reaction conditions, i.e. it does not interfere with the ortho-metallation reaction.
In the general formula (II) of the aromatic derivatives, the residue A can represent the residue of a monocyclic aromatic carbocyclic compound containing at least 4 carbon atoms and preferably 6 carbon atoms, or the residue of a polycyclic carbocyclic compound which can consist of at least 2 aromatic carbocycles and together forming ortho- or ortho- and peri-fused systems, or can consist of at least 2 carbocycles, at least one of which is aromatic, and together forming ortho- or ortho- and peri-fused systems. A naphthalene residue may be mentioned more particularly.
Residue A can bear one or more radicals Rxe2x80x2 on the aromatic ring.
The process of the invention applies most particularly to carbocylic aromatic derivatives substituted with at least one electron-donating radical featured by a group OR1.
In the present text, the expression xe2x80x9calkoxy groupsxe2x80x9d denotes, in a simplified manner, groups of the type xe2x80x94Oxe2x80x94R1 in which R1 has the meaning given above. R1 thus represents either a saturated, unsaturated or aromatic, acyclic aliphatic or cycloaliphatic radical or a saturated or unsaturated aliphatic radical bearing an aromatic or non-aromatic, cyclic substituent, or alternatively a trialkylsilyl radical.
The carbocyclic aromatic ether which is involved in the process of the invention preferably corresponds to formula (II) in which R1 in OR1, represents a saturated or unsaturated, linear or branched acyclic aliphatic radical.
More preferably, R1 of the aromatic ether represents a linear or branched alkyl radical containing from 1 to 12 carbon atoms and preferably from 1 to 6 carbon atoms, the hydrocarbon-based chain possibly being interrupted with a hetero atom (for example oxygen), with a functional group (for example xe2x80x94COxe2x80x94) and/or bearing a substituent.
The saturated or unsaturated, linear or branched acyclic aliphatic radical can optionally bear a cyclic substituent. The term xe2x80x9cringxe2x80x9d preferably means a saturated, unsaturated or aromatic carbocyclic ring, preferably a cycloaliphatic or aromatic ring, in particular a cycloaliphatic ring containing 6 carbon atoms in the ring, or a benzene ring.
The acyclic aliphatic radical can be linked to the ring by a valency bond, a hetero atom or a functional group as illustrated in the case of the definition of Rxe2x80x2.
The ring can be optionally substituted and, as examples of cyclic substituents, substituents such as Rxe2x80x2 whose meaning is specified for formula (IIa) may be envisaged, inter alia.
R1 can also represent a saturated carbocyclic radical or a carbocyclic radical comprising 1 or 2 unsaturations in the ring, generally containing from 3 to 8 carbon atoms and preferably 6 carbon atoms in the ring, the said ring possibly being substituted with substitutents such as those proposed for Rxe2x80x2.
R1 can also represent an aromatic carbocyclic radical, preferably a monocyclic radical generally containing at least 4 carbon atoms and preferably 6 carbon atoms in the ring, the said ring possibly being substituted with substituents such as those proposed for Rxe2x80x2.
The process of the invention applies most particularly to the aromatic ethers of formula (II) in which R1 represents a linear or branched alkyl radical containing from 1 to 4 carbon atoms, an arylalkyl radical or a trialkylsilyl radical.
As examples of radicals R1 that are preferred according to the invention, mention may be made of methyl or ethyl, benzyl and trimethylsilyl radicals.
The process of the invention applies more particularly to the aromatic ethers of formula (IIa): 
In formula (IIa), R1 preferably represents a linear or branched alkyl radical containing from 1 to 4 carbon atoms, preferably a methyl or ethyl radical, or an arylalkyl radical or a trialkylsilyl radical, and Rxe2x80x2 and n are as defined above.
Aromatic ethers of formula (II) or (IIa) in which:
n ranges from 0 to 2,
R1 represents a linear or branched alkyl radical containing from 1 to 4 carbon atoms, an arylalkyl radical and preferably a benzyl radical, or a trialkylsilyl radical,
R1 represents a linear or branched alkoxy radical containing from 1 to 4 carbon atoms, preferably a methoxy or ethoxy radical or a radical OR1 with R1 as defined above, are preferably involved in the process of the invention.
As illustrations of compounds corresponding to formula (II) or (IIa), mention may be made more particularly of:
monoethers such as anisole, ethoxybenzene (phenetole), propoxybenzene, isopropoxybenzene, butoxybenzene, isobutoxybenzene, benzyloxybenzene, 1-methoxynaphthalene, 2-methoxynaphthalene, 2-ethoxy-naphthalene; and substituted monoethers such as 1-methoxy-2-allyloxybenzene and phenoxytrimethylsilane;
diethers such as veratrole, 1,3-dimethoxy-benzene, 1,4-dimethoxybenzene, 1,2-diethoxybenzene, 1,3-diethoxybenzene, 1,2-dimethoxybenzene, 1,3-dipropoxybenzene, 1,2-methylenedioxybenzene, 1,2-ethylenedioxybenzene; 1,3-dibenzyloxybenzene; and 1,3-diphenolbise-trimethylsilyl;
triethers such as 1,3,5-trimethoxybenzene and 1,3,5-triethoxybenzene.
The compounds to which the process according to the invention applies in a more particularly advantageous manner are 1,3-dimethoxybenzene, anisole, 1,4-dimethoxybenzene, 1,2-dimethoxybenzene, 1,3-dibenzyloxybenzene and 1,3-diphenolbis-tert-butyldimethylsilyl.
As regards the compound of general formula (I), the compounds which are most particularly suitable for the invention are those in which R represents a linear or branched C1 to C10 alkyl group, C3 to C10 cycloalkyl group, C6 to C12 aryl group or C7 to C15 alkylaryl group, such as, for example, a benzyl radical.
More preferably, it is a C1 to C10 alkyl group and more preferably a C3 to C10 alkyl group in which the alkyl chain may possibly be interrupted with one or more oxygen atoms.
It is preferentially a chloroalkane and preferably chlorobutane or chlorooctane.
As regards the alkali metal used according to the invention, this may be sodium, lithium or potassium.
The process claimed is more particularly advantageous when sodium is used as alkali metal:
Specifically, it is quite probable that the reaction of the compound of general formula (I) with the alkali metal generates the carbanion Rxe2x88x92 which, by reaction with the carbocyclic aromatic derivative of general formula (II) or (IIa), leads to metallation of this derivative. However, in the case of the process claimed, the carbanion Rxe2x88x92 is advantageously generated in the presence of a carbocyclic aromatic derivative and thus reacts immediately with this derivative. Consequently, the process claimed makes it possible to significantly reduce the risks of spurious dimerization reactions, which are observed more particularly in the presence of sodium, and which consist of a reaction of the carbanion Rxe2x88x92 with a compound of general formula I.
This alkali metal can be introduced for the metallation reaction either in the form of a dispersion or in molten form.
The dispersed form, which is more advantageous in terms of reactivity, is generally preferred. This dispersed form, which is commercially available, can also be obtained in situ by vigorous stirring of the pre-fused metal.
The compound of general formula (I) is generally introduced in a proportion of at least one equivalent of the carbocylic aromatic derivative and preferably between about 1 and 2 equivalents. The alkali metal is present at between about 2 and 4 equivalents of the carbocyclic aromatic derivative and preferably between about 2 and 2.5 equivalents.
The reaction of the carbocyclic aromatic derivative with the compound of formula I and the alkali metal is carried out in an aprotic organic liquid which is inert under the appropriate reaction conditions.
As examples of solvents which are suitable for the present invention, mention may be made in particular of aliphatic or aromatic hydrocarbons, and aliphatic, cycloaliphatic or aromatic oxygen ethers.
As examples of aliphatic or cycloaliphatic hydrocarbons, mention may be made more particularly of paraffins such as, especially, hexane, heptane, octane, nonane, decane, undecane, dodecane, tetradecane or cyclohexane, and aromatic hydrocarbons such as, especially, benzene, toluene, xylenes, cumene, petroleum fractions consisting of a mixture of alkylbenzenes, in particular fractions of the Solvesso(copyright) type.
Aliphatic, cycloaliphatic or aromatic oxygen ethers, and more particularly diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl tert-butyl ether, dipentyl ether, diisopentyl ether, ethylene glycol dimethyl ether (or 1,2-dimethoxyethane), diethylene glycol dimethyl ether (or 1,5-dimethoxy-3-oxapentane); phenyl ether, benzyl ether; and dioxane, tetrahydrofuran (THF).
The preferred solvents are anhydrous aromatic hydrocarbons such as toluene, THF, xylenes and anhydrous analogues.
A mixture of organic solvents can also be used. Needless to say, the solvents selected should remain inert under the reaction conditions.
The concentration of the carbocyclic aromatic derivative in the medium can vary within a wide range. Thus, it may be between 5% and 40% by weight of the medium and is preferably about 20% by weight.
From a practical point of view, the ortho-metallation reaction is carried out by first loading the alkali metal into the organic solvent. The mixture is then kept stirring. Conversely, the consecutive addition of the carbocyclic aromatic derivative can be carried out according to two variants.
According to a first variant, the said derivative is introduced in the form of a mixture with the compound of general formula (I). This mixture is preferably added to the reaction medium gradually.
The other variant preferably selected consists in successively adding the carbocyclic aromatic derivative and then the compound of general formula (I).
Generally, the various compounds are introduced at a temperature of between xe2x88x9220xc2x0 C. and 50xc2x0 C. and preferably at room temperature. Subsequent heating of the reaction medium to a temperature of between 20xc2x0 C. and 100xc2x0 C. and more preferably between 40xc2x0 C. and 60xc2x0 C. may possibly be advantageous.
The reaction is generally carried out at atmospheric pressure. The reaction is preferably carried out under a controlled atmosphere of inert gases such as nitrogen or rare gases such as argon.
The progress of the metallation reaction may be monitored, where appropriate, by visualizing the disappearance of the alkali metal. At the end of the reaction, the metallated form of the carbocyclic aromatic derivative is present in the reaction medium in a dissolved form. Where appropriate, the excess alkali metal is neutralized.
The product of the ortho-metallation reaction is not isolated but rather is used in the form as generated to produce derivatives of the compound of general formula (II) or (IIa).
An organic compound capable of interacting with the said metallation product by electrophilic substitution is generally introduced into the reaction medium.
As non-limiting illustrations of organic compounds of this type, mention may be made in particular of the following compounds:
xe2x80x94SO2,
xe2x80x94CO2,
xe2x80x94CS2,
xe2x80x94(R5)2NCHO,
xe2x80x94(CH2O)nxe2x80x2, with nxe2x80x2 being an integer ranging from 1 to 3,
xe2x80x94paraformaldehyde,
xe2x80x94(R5O)2SO2,
xe2x80x94R5SiXxe2x80x2,
xe2x80x94ArCH2Xxe2x80x2,
xe2x80x94R5Sxe2x80x94Sxe2x80x94R5,
xe2x80x94R5SO2xe2x80x94Oxe2x80x94O2SR5,
xe2x80x94R5Xxe2x80x2,
xe2x80x94B(OR5)3,
xe2x80x94R5SO2Xxe2x80x2,
xe2x80x94ArCOXxe2x80x2,
with R5 representing a linear or branched C1 to C12 alkyl radical or a C3 to C12 cycloalkyl radical, or a trifluoromethyl radical, and Xxe2x80x2representing a halogen atom such as chlorine or bromine.
The reaction itself can be carried out in a conventional manner.
The electrophilic derivative is conventionally introduced in a proportion of about from 1.0 to 2 equivalents, relative to the metallated carbocyclic aromatic derivative, and preferably about 1 to 1.5.
The reaction can be carried out at a temperature of between 20xc2x0 C. and 80xc2x0 C. and preferably between 20xc2x0 C. and 50xc2x0 C. It is generally carried out at atmospheric pressure and under an inert atmosphere.
The reaction product can be isolated after the substitution reaction by any conventional technique of extraction type, for example.
One specific embodiment of the invention relates in particular to the preparation of 2,6-dimethoxybenzoic acid from 1,3-dimethoxybenzene.
More specifically, a subject of the present invention is a process for preparing 2,6-dimethoxybenzoic acid from 1,3-dimethoxybenzene via the ortho-metallation of the latter, characterized in that the said metallation is carried out by reacting 1,3-dimethoxybenzene with an alkali metal in the presence of a compound of general formula (I):
RXxe2x80x83xe2x80x83(I)
in which
R represents a hydrocarbon-based radical containing from 1 to 20 carbon atoms which may be a saturated or unsaturated, linear or branched acyclic aliphatic radical; a saturated, unsaturated, monocyclic or polycyclic cycloaliphatic radical; or a saturated or unsaturated, linear or branched aliphatic radical bearing a cyclic substituent; and
X represents a bromine or chlorine atom.
The alkali metal is as defined previously. It is preferably sodium.
According to one embodiment of the invention, it is combined with chlorooctane.
As regards the stoichiometry and the operating parameters which are suitable for carrying out the said metallation reaction, reference will be made to the information given previously.